Effects of FSGS factor on arachidonic acid metabolism

描述(由候选人提供)： 局灶性节段性肾小球硬化(FSGS)以大量蛋白尿为特征 并进展为终末期肾病。FSGS的发病率有所增加 在过去的20年里非常明显，并且是最常见的初诊原因 成人肾病综合征有几个系列。环氧合酶抑制剂 消炎痛减少FSGS患者的蛋白尿，涉及一种产品 花生四烯酸代谢作为蛋白尿的介体。 FSGS患者血浆中的一种低分子蛋白(简称 FSGS因子)增加了孤立肾小球的白蛋白通透性。在场 FSGS因子与疾病复发相关并预测疾病复发 同种异体肾移植。由我的K08基金资助的工作表明，FSGS 因子通过刺激花生四烯酸增加肾小球白蛋白通透性 酸性环氧合酶和血栓素A-2合成酶途径。此外，FSGS 因子从分离的肾小球释放花生四烯酸并刺激 前列腺素EZ合成。在初步研究中，我发现 磷脂酶A-2、环氧合酶-2和血栓素A-2的表达 注射FSGS因子的大鼠肾脏中的合成酶。建议进行的研究 将进一步探讨这一效应。具体目标是确定是否 FSGS因子在体内改变肾小球花生四烯酸关键酶的表达 酸代谢。 大鼠将被注射FSGS因子或相同比例的正常 血浆。肾组织(肾脏切片或孤立的肾小球)将在 不同时间点磷脂酶A2、COX-1、 用Western blotting和RT-PCR检测COX-2和血栓素A2合成酶。结果 将与肾小球白蛋白通透性和尿量相关 蛋白质和二十烷类化合物的排泄。 建议的实验结果将为下一步 磷脂酶A2、COX-1、COX-2转录调控的研究 和FSGS因子合成的血栓素A2合成酶。这些研究将提供 复发性FSGS患者蛋白尿的病理生理学研究 并可能为这些患者带来新的治疗策略。

DESCRIPTION (provided by candidate): Focal segmental glomerulosclerosis (FSGS) is characterized by heavy proteinuria and progression to end-stage renal disease. The incidence of FSGS has increased markedly over the past 20 years, and is the most common cause of primary nephrotic syndrome in adults in several series. The cyclooxygenase inhibitor indomethacin decreases proteinuria in patients with FSGS, implicating a product of arachidonic acid metabolism as a mediator of proteinuria. A low molecular weight protein in plasma of patients with FSGS (referred to as the FSGS factor) increases albumin permeability of isolated glomeruli. Presence of the FSGS factor is associated with and predictive of recurrence of disease in renal allografts. Work funded by my K08 grant demonstrated that the FSGS factor increases glomerular albumin permeability by stimulating the arachidonic acid cyclooxygenase and thromboxane A-2 synthase pathways. Also, the FSGS factor releases arachidonic acid from isolated glomeruli and stimulates prostaglandin EZ synthesis. In preliminary studies, I have shown increased expression of phospholipase A-2, cyclooxygenase-2 (COX-2) and thromboxane A-2 synthase in kidneys of rats injected with the FSGS factor. The proposed studies will further explore this effect. The Specific Aim is to determine whether the FSGS factor alters in vivo glomerular expression of key enzymes of arachidonic acid metabolism. Rats will be injected with the FSGS factor or an identical fraction of normal plasma. Kidney tissue (kidney slices or isolated glomeruli) will be examined at various time points for mRNA and protein levels of phospholipase A2, COX-1, COX-2 and thromboxane A2 synthase using Western blotting and RT-PCR. Results will be correlated with glomerular albumin permeability and with urinary excretion of protein and eicosanoids. Results of the proposed experiments will provide the groundwork for further studies to explore transcriptional regulation of phospholipase A2, COX-1, COX-2 and thromboxane A2 synthase by the FSGS factor. These studies will provide insight into the pathophysiology of proteinuria in patients with recurrent FSGS and may lead to novel treatment strategies in these patients.